The overall hypothesis of this project is that immuno-gene therapy can be used successfully to treat malignant pleural mesothelioma (MPM). The Project will continue to move the preclinical findings from Projects 2 and 3 into cutting-edge clinical trials (bench-to-bedside); and to provide clinical data and specimens back to Projects 2 and 3 to inform improvements in the next iteration of clinical trials (bedside-tobench). The first focus of this project is to continue and extend successful trials using intrapleural injections of an adenovirus (Ad) expressing type 1 interferon (Ad.lFN). Based on preclinical data from Project 2, a Phase 1/2 trial was initiated combining two Ad.IFN-alpha doses (given 3 days apart) with concomitant Celecoxib administration, followed two weeks later by 4-6 cycles of either front-line (pemetrexed/cisplatin/) or second-line (gemcitabine/carboplatin) chemotherapy. Aim 1 of this proposal is to complete the Phase 2 trial to determine if the response rate warrants moving this therapy to a larger randomized Phase 2 or 3 trial by either industry or cooperative groups. The second focus of the Project is adoptive T cell therapy using T cells with chimeric antigen receptors (CARs) initially targeted to the mesothelioma tumor surface antigen, mesothelin. Given potential safety concerns with some other CARs, a trial using T-cells transduced with GMP grade mRNA will be conducted (Aim 2A). Since CAR expression time is limited, if any off tumor effects occur, they will be very short lived. Once the safety of this approach is established, a larger trial using lentiviral-transduced CAR T cells in combination with lymphodepletion will be conducted (Aim 2B). The newly established Penn Mesothelioma and Pleural Disease Program (PMPDP) will play an important role in coordination of the multiple trials, in augmenting accrual, and in supporting patient travel expenses. Completion of these aims will generate new knowledge about human tumor immunology and provide novel data on the potential use of adoptive T cell transfer, especially the use of mRNA-transduced T cells. The ultimate goal is to change the treatment paradigm for mesothelioma and other similar cancers by showing that immunotherapy should be part of a multi-modality treatment armamentarium.